.alpha..sub.1 -Adrenergic receptors are widely distributed throughout both the central nervous system and the periphery where they mediate the effects of epinephrine and norepinephrine on the sympathetic nervous system. .alpha..sub.1 -Adrenoceptors play a central role in the maintenance of smooth muscle tone in both the prostate and the cardiovascular system (Ruffolo, R. R., Hieble, J. P. Pharmac. Ther. 1994, 61, 1-64). Antagonists of .alpha..sub.1 -adrenoceptors have shown beneficial effects both on ameliorating hypertension and alleviating the symptoms of benign prostatic hyperplasia (BPH) (Ruffolo, R. R., Bondinell, W., Hieble, J. P. J. Med. Chem. 1995, 38, 3681-3716) by producing a smooth muscle relaxant effect in the target organs resulting from blockade of vascular or prostatic .alpha..sub.1 -receptors.
Recently, three distinct subtypes of the .alpha..sub.1 -adrenoceptor have been identified by both molecular biological (.alpha..sub.1a, .alpha..sub.1b, .alpha..sub.1d) and classical pharmacological (.alpha..sub.1A, .alpha..sub.1B, .alpha..sub.1D) means. The functional expression of the .alpha..sub.1D -adrenoceptor subtype in various vascular beds has been demonstrated (Villalobos-Molina, R., Ibarra, M. Eur. J. Pharmacol. 1996, 298, 257-263; Piascik, M. T. et al. J. Pharmacol. Exp. Ther. 1995, 275, 1583-1589; Kenny, B. A. et al. Br. J. Pharmacol. 1995, 115, 981-986). Additionally, it has been shown that the .alpha..sub.1D -adrenoceptor plays a significant role in maintaining blood pressure (Zhou, L., Vargas, H. M. Eur. J. Pharmacol. 1996, 305, 173-176; Deng, X. F., Chemtob, S., Varma, D. R. Br. J. Pharmacol. 1996, 119, 269-276) and that its role in maintaining blood pressure increases with the age of the mammal (Ibarra, M. et al. Eur. J. Pharmacol. 1997, 322, 221-224). Therefore, the utility of a selective .alpha..sub.1D -antagonist in the treatment of hypertension is indicated (Deng et al.). Also, approximately 30% of the mRNA in the prostate encodes for the .alpha..sub.1D -adrenoceptor (Price, D. T. et al. J. Urol. 1993, 150, 546-541 which suggests a possible role in ameliorating the symptoms often associated with BPH. Additionally, it has been shown recently (Broten et al. The FASEB Journal Abstracts Part 1, (1998), 12 (4) A445) that the .alpha..sub.1D -receptor is involved in mediating contractions associated with detrusor instability secondary to bladder outlet obstruction. It has also been shown recently that the .alpha..sub.1D -receptor is the predominant .alpha..sub.1 subtype present in the human bladder detrusor (Malloy, et al. in J. of Urology, (1998) 159, (5, Suppl.) 1263). The association of incontinence and the irritative symptoms of BPH with detrusor instability suggests that an .alpha..sub.1D -antagonist capable of inhibiting detrusor contractions would be useful in the treatment of incontinence and BPH.
Russell and Press (U.S. Pat. No. 4,670,560 and J. Med. Chem. 1988, 31, 1786) describe thienopyrimidine-2,4-dione derivatives which are .alpha..sub.1 -antagonists and antihypertensive agents, and Meyer et al. (U.S. Pat. No. 5,521,181) describe phenyl substituted hexahydrobenz[e]isoindolylthienopyrimidine-2,4-diones which are .alpha..sub.1 -antagonists. However, these compounds are not selective for the a .alpha..sub.1D subtype.
The present invention relates to novel .alpha..sub.1D adrenoceptor antagonist compounds, pharmaceutical compositions containing the compounds, and methods of treatment using these compounds.